Chronic hepatitis is a severe hepatic disease which forms hepatocirrhosis and hepatic carcinoma. Most cases of chronic hepatitis are caused by infection with hepatitis C virus (HCV). Interferon (IFN) therapy presently is used to treat chronic hepatitis C. Although its severe side effects are known, long-term administration of IFN for 4 to 6 months is necessary and has limited therapeutic effect. For example, studies of the effect of IFN therapy and of the properties of HCV, report that IFN therapy has a significant effect on the type III genotype virus (10 to 20% prevalence in Japan) but has only 20 to 30% effectiveness against the type II genotype virus, which represents at least 70% of the virus in Japan [Iino et al., Saishin Igaku, 99, 2225 (1993)]. Accordingly, there is a need for a new therapy for the latter patients for whom IFN therapy is not effective.
The inventors studied the mechanism of the onset of hepatic disorders, using the LEC rat as a model animal with human hepatic carcinoma generated from chronic hepatitis. These studies revealed that feeding an LEC rat with conventional feed having metallic ions such as copper, iron etc. stimulated a rapid increase in hepatic copper as well as an increase in hepatic iron levels, thus causing a high incidence of severe hepatitis. On the other hand, feeding an iron-deficient feed caused only a slight increase in hepatic iron, and no observable severe hepatitis, although hepatic copper levels rapidly increased in a similar manner to the case of feeding with conventional feed. From these results, indicated that the major factor causing hepatic disorders is an abnormal increase of iron ions in the liver [Kofune et. al., Lecture Summary of the 53rd Meeting of Japanese Cancer Society, page 91, 1994]. Actually, chronic active hepatitis C can subside by removing iron ions through venesection [Takigawa et al., Summary Collection of the 27th western Sectional Meeting of Japanese Hepatic Society, Vol. 33, Supple (2), page 49, 1992] and a non-IFN responsive hepatitis can be changed into IFN responsive hepatitis through venesection [Hayashi et al., Igaku To Yakugaku, 29, 1487 (1993)]. However, although rapid venesection effectively reduces hepatic iron levels, it causes anemia. This anemia makes continued treatment difficult due to worsening of general conditions of the patient. Furthermore, when venesection is conducted to limit anemia in the patient, a long period of 1 or 2 years is required to obtain a sufficient therapeutic effect. During this long time period, however, chronic hepatitis often is transformed through hepatocirrhosis into hepatic carcinoma. Accordingly, there is a strong demand to develop therapies to improve hepatic functions as rapidly as possible.
It is further reported that one of antigens as cancer markers is a transferring receptor [Trowbridge, I. S. and Omary, M. B., Proc. Natl. Acad. Sci. USA, 78, 3039-3043 (1981)]. Some of the present inventors have reported that transferrin receptors occur abundantly in actively proliferating cancer cells, and that the presence of these transferrin receptors indicates the ability of cells to proliferate, or the malignancy of cancer cells [J. Jpn. Cancer Ther. 21(3), 641-646, Apr. (1986)]. Thus, so it is reasoned that a high iron ion concentration is required for cancer cells to actively proliferate.
Meanwhile, erythropoietin administration is proposed to treat a blood pigment symptom caused by blood-transfusion for improvement of chronic anemia resulting from renal functional disorders. In this case, erythropoietin is administered into anemic patients undergoing hemodialysis before their stored iron and serum iron are decreased as a result of venesection (Japanese Patent Publication No. 92316/1994). However, no report clarifies whether the hepatic functions of patients suffering hepatic disease such as chronic hepatitis or hepatic carcinoma are improved by erythropoietin administration.
Accordingly, the object of the present invention is to clarify the relationship between hepatic iron metabolism and erythropoietin to improve thereby and shorten treatment time. Another object is to provide a pharmaceutical composition for treatment of hepatic diseases which comprises erythropoietin as an active ingredient.